Craniofacial diseases are some of the most common of human birth defects and can be extremely variable in their severity and extent. There are both genetic and environmental causes of craniofacial disease and it is likely that a large portion of disease variability is due to gene/environment interactions. It is our long-term objective to understand the mechanism of gene/environment interactions and how these interactions regulate disease severity. We have chosen to use Fetal Alcohol Syndrome (FAS) as a model of gene/environment interactions because FAS has variable craniofacial defects, has a known environmental cause (maternal alcohol consumption) and is clearly genetically regulated. However, we are lacking in our understanding of the genetic loci that control susceptibility to ethanol-induced craniofacial disease. We have utilized two innovative genetic screens to discover ethanol-interacting loci. Results from these screens demonstrate that the platelet-derived growth factor rector a (pdgfra) and ethanol-induced jaw hypoplasia (eih) loci interact synergistically with ethanol. While untreated pdgfra mutants have cleft palate, our first genetic screen demonstrated that ethanol-treated pdgfra mutants have profound and extensive craniofacial defects. Furthermore, ethanol-treatment causes palatal defects in pdgfra heterozygotes. We have shown that neural crest cells fail to migrate properly in untreated pdgfra mutants, but in ethanol treated pdgfra mutants and heterozygotes there is an increase in the amount of cell death. In a second genetic screen, we have found that ethanol-treated eih and Bone morphogenetic protein (Bmp) loss-of-function embryos have a jaw-loss phenotype similar to that in mutants that disrupt development of the anterior endoderm. Here, we determine the mechanisms for these interactions. In aim 1, we discover which Platelet-derived growth factor (Pdgf) family members regulate the severity and extent of craniofacial disease. In aim 2, we reveal the intracellular signaling events that are responsible for the separate migratory and protective roles that pdgfra plays in neural crest cells. In aim 3, we explore how eih interacts with the Bmp signaling pathway and we determine the extent to which ethanol disrupts endoderm development in eih and bmp morpholino injected embryos. Because of the conservation of gene function between zebrafish and humans, the results from our studies will provide key insights into the genetic loci that interact with the environment to modulate human craniofacial disease severity. ) PUBLIC HEALTH RELEVANCE: Virtually nothing is known about how gene-environment interactions mediate human disease. Our studies will provide some of the very first insights into the mechanisms of gene/environment interactions. The results we obtain will translate directly to human disease, providing candidate loci for association studies, risk factors for genetic counseling and potential therapies.